Summary ? Project 2 Type-2 diabetes mellitus (T2DM) is a growing health-related concern, in part because of increases in its incidence. However, T2DM is also significant because of emerging evidence regarding the breadth of its effects on various body systems. It is now recognized that T2DM is associated with CNS deficits such as dementia, including Alzheimer's disease. We have found several ways in which a gene related to Alzheimer's influences diabetic tendencies in mice. The amyloid precursor protein (APP) serves as the source of amyloid ?-peptide (A?), and its mutation is capable of causing Alzheimer's. Our preliminary studies indicate that APP exerts a powerful impact on insulin/glucose metabolism, so to test the role of A? itself, we have turned to mice that over-produce this peptide alone in the CNS. These mice develop a prediabetic state (insulin resistance) by default. We propose to determine the effects of A? on CNS elements that control peripheral energy metabolism, placing particular emphasis on inflammatory processes. We also will test whether any effects of A? on insulin/glucose regulation can be modulated by expression of human apolipoprotein E (ApoE). This protein's gene (APOE) contributes the largest demographic risk to Alzheimer's disease, and ApoE both impacts inflammation and binds A? in genotype-specific manners. Thus, we expect ApoE to modify the effects that A? has on insulin/glucose metabolism. Finally, we will test whether the effects of A? on insulin/glucose metabolism can be similarly modified by interrupting inflammation or protein aggregation; this will be accomplished in part through cooperative strategies for drug development throughout the parent Program. Together, these experiments will characterize the interactions between T2DM-related syndromes and proteins of critical importance to Alzheimer's disease. The project will ultimately test pharmacological agents that directly impact these interactions and may thus provide novel therapeutic opportunities for Alzheimer's and T2DM.